Abstract 3651: The role of caspase-1 in basal-like breast cancer and the tumor microenvironment
Authors: Wanda Marini, Weiyue Zheng, Kiichi Murakami, Pamela S. Ohashi, Michael Reedijk
Journal: Cancer Research (2023)

Abstract Introduction: Breast cancer is the most common malignancy in women world-wide. Basal-like breast cancer (BLBC) is an aggressive subtype with poor prognosis for which there are no known targeted therapies. Understanding what drives complex cell-cell interactions within the tumor microenvironment (TME) is critical to developing new strategies. BLBC has previously been shown to have high expression of the inflammatory cytokine IL1β, which then promotes the recruitment of pro-tumoral tumor-associated macrophages (TAMs) to the TME. Here we report that BLBC is uniquely capable of IL1β secretion due to elevated expression of caspase-1, a key component of the inflammasome required for IL1β maturation. Methods: Using publicly available gene expression data sets, the association between caspase-1, breast cancer subtype and estrogen receptor (ER) co-expression was examined. These associations were further assessed in vitro by exposing luminal (T47D/MCF7) or BLBC (MDA-MB231) cell lines to siER knockdown or ER overexpression. Using both a CRISPR/Cas9 generated caspase-1 knockout (KO) BLBC mouse line as well as pharmacological inhibition with the caspase-1 inhibitor VX-765, the effect of caspase-1 on tumor growth was studied in syngeneic immunocompetent mice. Immune infiltrates were assessed via flow cytometry of the excised murine tumors as well as immunohistochemistry. To prove these results were IL1β specific, caspase-1 KO tumor allografts containing self-cleaving IL1β were used for comparison. Finally, to determine potential synergy between caspase-1 and immune checkpoint inhibition, wild type and caspase-1 KO allografts were simultaneously treated with anti-PD1 immunotherapy. Tumor growth and immune infiltrates were analyzed between the treatment groups as stated above. Results: Caspase-1 was found to be associated with the basal-like subtype and have an inverse relationship with ER expression. In vitro, inhibition of ER increased caspase-1 expression, whereas ER overexpression decreased caspase-1. Caspase-1 KO or pharmacological inhibition resulted in a significant decrease in tumor growth and TAM infiltration, and these findings were rescued back to wild type levels with the addition of a self-cleaving IL1β. Finally, caspase-1 inhibition reversed resistance to anti-PD1 immunotherapy in murine allografts, resulting in significant deceleration of tumor growth when used in combination. Summary: The lack of ER in BLBC promotes caspase-1 expression, allowing IL1β maturation, macrophage recruitment and tumor progression. Genetic or pharmacologic inhibition of caspase-1 inhibits TAM recruitment and reverses resistance to immune checkpoint inhibition in BLBC. Conclusions: Our data provides new insights into the biology of BLBC and identifies the combination of caspase-1/IL1β inhibition and immunotherapy as a novel therapeutic strategy to combat this disease. Citation Format: Wanda Marini, Weiyue Zheng, Kiichi Murakami, Pamela S. Ohashi, Michael Reedijk. The role of caspase-1 in basal-like breast cancer and the tumor microenvironment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3651.